"The Diffusionists Have Landed"(January 2000)
You've probably heard of those crackpot theories about ancient Phoenicians or Chinese in the New World. Maybe it's time to start paying attention. By Marc K. Stengel

"DNA Fatigue"(November 1997)
Worn out by a nucleotidal wave. By Cullen Murphy

"Moving Toward the Clonal Man"(May 1971)"The notion that man might sometime soon be reproduced asexually upsets many people.... Until recently, however, this foreboding has seemed more like a science fiction scenario than a real problem which the human race has to live with." By James D. Watson

"The History of Everyone and Everything" (Stanford Magazine, May-June 1999)
"He invented 'genetic geography' and tracks human migrations around the globe. But critics now charge that Luca Cavalli-Sforza wants to go too far." By Mitchell Leslie

American Society of Human Genetics
"The American Society of Human Genetics (ASHG), founded in 1948, is the primary professional membership organization for human geneticists in North America. Members include researchers, academicians, clinicians, laboratory practice professionals, genetic counselors, nurses, and others involved in human genetics." The site offers information about the organization and its publications, and the full text of articles from The American Journal of Human Genetics.

Human Genome Organization [HUGO]
"HUGO is the international organisation of scientists involved in the Human Genome Project.... Activities range from support of data collation for constructing genetic and physical maps of the human genome to the organisation of workshops to promote the consideration of a wide range of ethical, legal, social and intellectual property issues."

Blueprint of the Body
A CNN.com report on human gene mapping and its implicatioins. The site offers a general overview, a collection of essays, archives of video footage and articles, links to related sites, and transcripts of live chats with experts.

Stanford Human Genome Center
The Web site of Stanford University's Human Genome research center. The site offers information about ongoing gene mapping and sequencing research, and opportunities for scientists to contribute mapping information over the Web.

Rural Advancement Foundation International [RAFI]
The Web site of an organization "dedicated to the conservation and sustainable improvement of agricultural biodiversity, and to the socially responsible development of technologies useful to rural societies." The site offers general information about the organization, news bulletins, exhortations to action, and publication-ordering information.

Institute for Agriculture and Trade Policy: Intellectual Property Rights
A collection of papers speaking out against the coopting of intellectual property rights inherent in genetic information by corporations and governments. Posted by the Institute for Agriculture and Trade Policy, an organization that "promotes resilient family farms, rural communities and ecosystems around the world through research and education, science and technology, and advocacy."

Indigenous Peoples Council on Biocolonialism
"The IPCB is organized to assist indigenous peoples in the protection of their genetic resources, indigenous knowledge, cultural and human rights from the negative effects of biotechnology." The site offers news, press releases, and general information about the organization.

Anthropology, Genetic Diversity, and Ethics
Transcripts from a 1999 workshop at the University of Wisconsin-Milwaukee designed "to facilitate communication among researchers involved in studies of genetic diversity, ethicists and attorneys specializing in genetic and biomedical issues and members of some of the involved communities, including some opponents of genetic research in identified populations."

The Atlantic Monthly | April 2001

The Genetic Archaeology of Race
DNA analysis is explaining where "racial difference" comes from—and what it does and doesn't mean. The study of human genetic variation has become the most contentious area in modern science

by Steve Olson

.....

ver the past decade or so genetics researchers have been undermining the widespread belief that groups of people differ genetically in character, temperament, or intelligence. They have shown that all human beings are incredibly similar genetically—much more so than other species of large mammals. They have revealed the folly of attributing group behavioral differences to biology rather than culture.

But that's not how many of the news stories have read. On the contrary, here are the kinds of headlines you might have seen: "RESEARCHERS FIND GENETIC MARKER UNIQUE TO AFRICANS." "ASIANS BIOLOGICALLY LESS SUSCEPTIBLE TO ALCOHOLISM." "ALL NATIVE AMERICANS DESCENDED FROM A SMALL NUMBER OF FOUNDERS." In other words, given how journalists, pundits, and bigots have interpreted genetics research, people are probably more convinced than ever that group differences are significant.

We will continue to be inundated with DNA-sequence information—and with interpretations of that information—for many years to come. These genetic data have immense medical potential (though that potential will probably take much longer to realize than most people suspect). By studying the genetic differences among individuals, researchers will eventually find many DNA variants that contribute to health or disease.

But genetics research is also producing results of an entirely different kind. Differences in DNA sequences from person to person reflect the cumulative effects of human history. The patterns of genetic variation in the world today therefore carry a record of that history. They document the evolution of an African ape that began walking on two legs about four million years ago. They record the existence, sometime between 100,000 and 200,000 years ago, of a small group of people who are the ancestors of every person alive today. They chronicle the origins of "races" and "ethnic groups" and describe how those groups have both blended and separated over time.

Most genetics researchers are well aware of the historical dimensions of their work. But because these considerations raise uncomfortable issues, particularly issues of race, they tend to be downplayed. The White House news conference held on June 26 of last year to celebrate the sequencing of the human genome was filled with stirring but vague homages to human unity. "The human genome is our shared inheritance," said Francis Collins, the head of the publicly funded Human Genome Project, at the National Institutes of Health. "Race has no genetic or scientific basis," said Craig Venter, whose company, Celera Genomics, has been sequencing and analyzing human DNA.

The reality is considerably more complex. Genetics research is demonstrating that the differences in appearance among groups are profoundly incidental, but these differences do have a genetic basis. And although it's true that all people have inherited the same genetic legacy, the genetic differences among groups have important implications for our understanding of history and for biomedical research. These complications in an otherwise reassuring story have thoroughly spooked the leaders of the public and private genome efforts. The NIH has been collecting information about genetic variants from different ethnic groups in the United States, but it has refused to link specific variants with ethnicity. Celera has been sequencing DNA from an Asian, a Hispanic, a Caucasian, and an African-American, but it, too, declines to say which DNA is which.

This strategy of avoiding the issue is almost sure to backfire. It seems to imply that geneticists have something to hide. But the message emerging from laboratories around the world should be hailed, not muzzled. It is one of great hope and promise for our species.

ne reason for the caution displayed by the genome sequencers is a largely overlooked drama that has been playing out on the fringes of the Human Genome Project for the past ten years. Unlike most scientific dramas, this one has a clear protagonist: Luigi Luca Cavalli-Sforza, a genial but sharp-tongued professor of genetics at Stanford University. Now seventy-nine, with thick silver hair and a perpetually inquisitive expression, Cavalli-Sforza combines the demeanor of a man accustomed to respect with a natural openness that has won him many friends. Born and educated in Italy, he went to Stanford University in 1971. There he quickly became a leader in the fledgling field of anthropological genetics, which draws inferences about the past based on the patterns observed in human DNA. His former students are now scattered around the world, carrying on the work he began. Yet he still rides his bike to campus each morning to write, read, and analyze the latest results from the lab. "He'll work until he drops," an associate says. "He's curious about the science."

In 1991 Cavalli-Sforza and a group of colleagues proposed a comprehensive study of human genetic differences, which they called the Human Genome Diversity Project. The study would involve gathering cells from several thousand people around the world, "immortalizing" the cells by converting them into laboratory cell lines, and using the cells' DNA to reconstruct human evolution and history. For Cavalli-Sforza, the Human Genome Diversity Project was to be the culmination of a lifetime of work.

The proposal loosed a flood of controversy. Aboriginal groups in the United States, New Guinea, and other countries accused the HGDP of stealing their genes, destroying their culture, and even contributing to genocide. Academic critics claimed that the project could encourage racist thinking, by oversimplifying issues of great complexity. "The idea of studying human genetic diversity is a good one," says one outspoken critic, Jonathan Marks, an anthropologist at the University of North Carolina at Charlotte. "But the way that Cavalli-Sforza has conceptualized it has problems at all levels."

Cavalli-Sforza has been baffled by the reaction to his proposal. He has always believed that the HGDP will help to end racism, not inflame it. In the 1970s he participated in public debates with the Stanford physicist William Shockley to dispute Shockley's racist ideas. He has worked closely with various African groups and cares deeply about their well-being. He protests that his intentions have always been purely scientific.

For almost a decade Cavalli-Sforza has been trapped in the paradox at the heart of human genetics: The only way to understand how similar we are is to learn how we differ. Yet any study of human differences seems to play into the hands of those who would accentuate those differences. Researchers might claim that the genetic differences they identify among groups have no biological significance. Yet simply by dividing human beings into categories—whether sub-Saharan Africans, Jews, Germans, or Australian aborigines—they reinforce the distinctions they would seek to minimize. How to resolve this dilemma is quickly becoming one of the most difficult problems facing the study of human genetics.

A Theory of Mutation

ore than 10,000 years ago, on the frigid, wind-swept plains of northeastern Siberia, a genetic accident occurred in a testicle of a particular man. As one of the man's sperm cells divided, the Y chromosome in the cell underwent a copying error. One of the chemical units making up his DNA changed from a molecule called cytosine to one called thymine. An elaborate biochemical proofreading apparatus is supposed to correct such copying errors, which geneticists call mutations. But there are so many individual chemical units, or nucleotides, in human DNA—about 60 million in the Y chromosome, and about three billion in the other chromosomes in a human sperm or egg cell—that a few mutations inevitably creep in every time a cell divides.

Within the next couple of months the man impregnated a woman. The sperm cell that combined with her egg was the one with the mutated Y. The woman gave birth to a son, each of whose cells had the mutated Y he got from his father. The son was no different from the other men in his tribe (the mutation in his Y had no effect on his body), yet he was a pivotal figure in human genetic history.

At some point, according to one interpretation of events, the son of the man whose Y had mutated crossed what was then a broad plain leading from Asia to North America—presumably with a small band of others. Before him stretched a continent that was largely, or perhaps completely, devoid of human beings. This man had sons himself, and his sons had sons. Over subsequent centuries his descendants spread down the length of North America, across the Isthmus of Panama, and into South America. All of them carried their forebear's distinctive Y chromosome, to which they added their own mutations. Today more than half of Native American males have this mutated Y chromosome.

Genetic reconstructions of historical events can always be interpreted in somewhat different ways, observes Peter Underhill, the geneticist in Cavalli-Sforza's lab who first detected this and many other variations in Y chromosomes. The mutation could have occurred in Siberia some generations before the migration along the Bering land bridge, or it could have occurred in North America. Nevertheless, we know that this man existed and that his Y chromosome differed from any previous Y chromosome in this way. His particular mutation could not have originated in more than one of the ancestors of today's Native Americans, and the mutation occurred in no other group in the world. Yet DNA is such a long and complex molecule that every act of human procreation produces at least some unique mutations. These mutations spill across the generations like an unusually shaped jaw or distinctively colored eyes. The result is an elaborate human genealogy, an intricately branching tree of genetic alterations.

hen Cavalli-Sforza first became interested in genetics, the detailed mechanisms of human heredity were completely unknown. In 1938, at the age of sixteen, he had enrolled in medical school at the University of Pavia, in Italy, largely because of a fascination with microscopes. "It turned out to be a very lucky choice," he says. "Had I not gone to medical school, I would have been conscripted at the beginning of the war."

But when he graduated, in 1944, he found that he disliked the practice of medicine. So he took a part-time faculty position at the University of Parma and did research on bacterial genetics. He is still well known among geneticists for his contributions to the discovery that microbes have sex—or at least can engage in the kind of genetic exchanges involved in human couplings.

In 1951 a chance remark by one of his students redirected his research toward human beings. "Throughout my life I've been very lucky in finding good students," he recalled recently, when I met with him in his office at the Stanford medical school. "This particular student was also a priest. He mentioned to me that there were some data he thought would be of interest for human genetics." For more than three centuries the Catholic Church had collected information on births, marriages, and deaths in many Italian parishes. It was the ideal data set, Cavalli-Sforza realized, for the study of a particularly contentious issue in twentieth-century genetics—the role of genetic drift in evolution.

Most descriptions of evolution emphasize natural selection, in which a beneficial mutation becomes more common over time because bearers of this mutation are more likely to survive and procreate. But if an organism just happens to have lots of descendants, its genetic variants will become more common whether they are selected for or not. That's what happened with the Siberian forefather of many Native Americans. His Y chromosome did not have an advantage over any others—it simply prospered through the vagaries of genetic chance.

In the 1950s many geneticists believed that natural selection would almost always squelch genetic drift. The parish records gave Cavalli-Sforza a way to test the idea. They showed that most people in the mountain valleys high above Parma married within their own small villages. Genetic drift is more obvious in small, relatively insular populations, because an individual who happens to have lots of children can flood a population with his or her distinctive genetic variants. In contrast, on the plains around the university, for example, the genetic effects of any one person are reduced, because the population is larger and more mixed. There genetic drift should be less obvious.

One way to measure genetic drift is to look at the relative proportions of blood types within certain communities. So Cavalli-Sforza and a few assistants took needles and test tubes and fanned out over the countryside. With the help of parish priests they gathered blood samples, often in sacristies after Sunday mass. They found that the distribution of blood types varied much more from village to village in the mountains than in the valley, just as predicted by the theory of genetic drift.

His success led Cavalli-Sforza to consider the matter more broadly. If he could link genetics with mating and migrations among the people around Parma, why couldn't he do the same thing on a larger scale? In fact, he ought to be able to determine the genetic relationship between any two groups of people. A group should carry many of its predecessors' variants, just as children bear the genetic legacies of their parents. By detailing the genetic similarities and differences among groups, Cavalli-Sforza could trace humanity's spread across the planet.

More and more kinds of blood were being discovered in the 1950s. In 1961 Cavalli-Sforza decided that he had enough data to try his idea. He and a colleague analyzed published data on blood types in fifteen populations—three each from Europe, Africa, Asia, and the Americas, and one each from Australia, New Guinea, and New Zealand—and produced a tree showing how the various groups were related.

The results looked reasonable. The Native Americans from Venezuela and Arizona were related to Eskimos and Koreans in the sample, squaring with a migration across what is now the Bering Strait. The Africans and Europeans were genetically close, reflecting their continents' relative proximity. But to find out more, Cavalli-Sforza needed new kinds of data.